Pharmacokinetics of Flumazenil and Midazolam

Abstract

We have studied simultaneously the pharmacokinetics of flumazenil and midazolam in 12 healthy Chinese children, aged 5-9 yr, undergoing circumcision. Two hours before operation each patient received midazolam 0.5 mg kg-1 orally for premedication and 0.5 mg kg-1 i.v. during induction. Six minutes after cessation of anaesthesia, a bolus of flumazenil 10 micrograms kg-1 was given i.v., followed by an infusion of flumazenil at 5 micrograms kg-1 min-1 which was maintained until the child could identify himself. Midazolam data were consistent with a three-compartment model with a mean (SD) elimination half-life of 107 (30) min, total body clearance of 15.4 (3.2) ml min-1 kg-1 and apparent volume of distribution at steady state of 1.9 (0.6) litre kg-1. Flumazenil data were best interpreted by a monoexponential function, with a mean terminal elimination half-life of 35.3 (13.8) min, a total plasma clearance of 20.6 (6.9) ml min-1 kg-1 and apparent volume of distribution at steady state of 1.0 (0.2) litre kg-1. No unchanged midazolam was detected in the 24-h urine sample, but 5.8-13.8% of the flumazenil dose was recovered unchanged. At the time of self identification, 4.5 (1.4) min after flumazenil administration, the mean plasma concentrations of midazolam and flumazenil were 163.1 (43.7) and 29.9 (16.1) ng ml-1, respectively.

Effect of flumazenil on recovery from sevoflurane anesthesia in children premedicated with oral midazolam before undergoing herniorrhaphy with or without caudal analgesia

“…In that study, the mean total dose of flumazenil administered to achieve awakening was 0.024 mg · kg -1 , whereas other investigators used flumazenil 0.017-0.027 mg · kg -1 to antagonize the effect of midazolam [9,16]. Therefore, we administered flumazenil at a fixed dose of 0.02 mg · kg -1 .…”

Safety and Efficacy of Flumazenil for Reversal of Iatrogenic Benzodiazepine-Associated Delirium Toxicity During Treatment of Alcohol Withdrawal, a Retrospective Review at One Center

“…Benzodiazepines are γ-aminobutyric acid type A (GABA-A) receptor agonists which bind to sites in the central nervous system (CNS) and exert sedative and amnestic effects [1][2][3]. These inhibitory CNS effects are useful during the treatment of alcohol withdrawal syndrome (AWS), but can also result in dose-dependent CNS depression and even frank delirium.…”

“…These inhibitory CNS effects are useful during the treatment of alcohol withdrawal syndrome (AWS), but can also result in dose-dependent CNS depression and even frank delirium. Flumazenil, a benzodiazepine receptor antagonist, effectively reverses benzodiazepine-induced CNS depression via competitive inhibition at the GABA-A receptor-binding site [2][3][4][5][6][7][8]. Flumazenil has been beneficial for expediting patient recovery from anesthesia [9][10][11] and was previously studied in 519 patients at our center; of which, 15 were diagnosed with alcohol withdrawal [12].…”

Inter-individual variation in midazolam clearance in children

“…16 24 25 28 Ethnicity was described in only four studies 1516 24 30 All studies except two were population PK studies. Six papers stated the CV 14…”

“…16 20 22 29 31 In nine papers, only the SD was reported and therefore CV was estimated assuming normal distribution 1120 25–28 30 33 34 The CV for all paediatric age groups ranged between 13% and 170% (figure 2). …”